Substance-specific treatments of fluids are becoming increasingly significant for applications such as biotechnology, medicine, and chemical technology. Fluids include gases, gas mixtures, and liquids such as protein solutions, prefiltered suspensions, and clear solutions. An example of substance-specific treatment is the extraction of active agents from cell suspensions in which genetically modified cells have generated substances such as antibodies, hormones, growth factors, or enzymes, usually in small concentrations. Other important applications are the extracorporeal removal of undesired substances from human blood plasma and extraction of components such as immunoglobulins or clotting factors from the plasma of donated blood. Finally, another broad application area is the catalytic or biocatalytic--enzymatic--treatment of liquids, such as the hydrolysis of oils by lipases immobilized in a matrix.
The substance-specific treatment of fluids is frequently conducted such that the fluid to be treated is brought into contact with a carrier material, on and/or in which interacting groups or substances are immobilized that, in a specific, selective manner, interact with the target substance contained in the fluid, i.e., with the substance that is the object of the substance-specific treatment. Such interactions can be, for example, cationic or anionic exchange, hydrophilic/hydrophobic interaction, hydrogen bridge formation, affinity, or enzymatic or catalytic reactions, and the like. In affinity separation of substances, ligands are coupled to or immobilized in the carrier material and have the function of adsorptively binding a specific single target substance or an entire class of substances. This target substance is termed a ligate. One example of class-specific ligands are positively charged diethylaminoethyl (DEAE) groups or negatively charged sulfonic acid (SO.sub.3) groups, which adsorb the class of positively charged or negatively charged molecules, respectively. Specific ligands are, for example, antibodies against a certain protein, which is bound as a ligate to the antibody.
The major criteria in the substance-specific treatment of fluids are productivity and selectivity. With a view toward productivity, it is important that, per unit of volume, as many groups as possible are available that act in a substance-specific manner and can interact with the target substance contained in the fluid to be treated. At the same time, it is desirable to maximize the transport of the target substance to the groups or substances acting in a substance-specific manner.
One carrier material for ligands that is frequently employed in affinity chromatography is sepharose particles, which are present in bulk form in a chromatographic column. Even if a high concentration of ligands, with high selectivity, can be realized in this case, the productivity is known to be low due to the compressibility of the sepharose particles. Furthermore, the access of the ligates to the ligands contained in the sepharose particles is diffusion controlled, which results in long residence times and thus low throughput and productivity, in particular when separating larger molecules such as proteins, due to their low diffusion rates.
Improved chromatographic column materials made from rigid, porous particles through which convective flow is possible are described in U.S. Pat. No. 5,019,270. Compared to the previously cited column material, these particles permit a reduction of residence time and increased productivity. However, even chromatographic columns filled with these particles exhibit with larger-diameter column diameters a non-uniform flow rate that has a negative effect with respect to the uniform utilization of all the ligands present in the chromatographic column. Furthermore, technical control of the pressure required becomes more complex as the diameters increase.
The cited disadvantages of particle-shaped carrier materials led to the development of a number of processes for substance-specific treatment of fluids using porous, semipermeable membranes. Due to their porous structure, membranes present a large inner surface area, so that a large number of functional groups can be coupled to the membrane, in high concentration per volume unit, which can interact with the fluids to be treated that flow through the membrane (see, for example, E. Klein, "Affinity Membranes", John Wiley & Sons, Inc., 1991; S. Brandt et al., "Membrane-Based Affinity Technology for Commercial Scale Purifications", Bio/Technology Vol. 6 (1988), pp. 779-782).
Membranes are available that are made from a wide variety of materials and with varying pore structures, so that adaptation to the physico-chemical properties of the fluids to be treated and convective transport through the membrane of the fluid to be treated, for example with a target substance contained therein, is possible. Moreover, due to the generally thin walls (&lt;100 .mu.m, for example), membranes are distinguished by short transport distances of the fluid to be treated to, for example, the interacting groups immobilized in the membranes, resulting in relatively short residence times, low pressure losses, high linear flow rates, and thus high binding rates.
A number of modules containing such membranes have been described that are used in processes for substance-specific treatment of fluids. In this case, a distinction must be drawn between so-called dead-end mode, or dead-end modules, and cross-flow mode, or cross-flow modules.
In the cross-flow mode, the fluid flows as a feed stream parallel to one side of the membrane. A portion of the feed stream thereby passes through the membrane. The partial stream after passing through the membrane is drained off as a permeate, and the portion remaining on the feed stream side as a retentate. On the permeate side of the membrane as well, an additional fluid stream can be introduced that then absorbs the partial stream after it passes through the membrane.
In dead-end mode, on the other hand, the entire fluid entering the membrane module as a feed stream is directed through the membrane and removed as a filtrate or permeate from the downstream side of the membrane opposite the upstream side.
Dead-end membrane modules on the basis of hollow-fiber membranes are used extensively for applications in the fields of ultra- or microfiltration and often for treatment of liquids with gases, for example. In one part of these membrane modules, as described in EP-A-0,138,060 or EP-A-0,659,468; for example, the hollow-fiber membranes have been folded in a U-shape and their ends embedded jointly in a sealing compound and open. The gas or liquid to be filtered flows, for example, via the open ends into the lumina of the hollow-fiber membranes and, due to the prevailing pressure differential, permeates into the external space surrounding the hollow-fiber membranes. In the case of filtration applications, the component that is filtered out remains in the membrane.
In another embodiment of dead-end membrane modules, the hollow-fiber membranes are arranged substantially linearly in the housing and their open ends are embedded jointly in a sealing compound, while their other ends are free, i.e., not embedded. The unembedded ends of the hollow-fiber membranes are closed in these modules. Such membrane modules are described in U.S. Pat. No. 4,002,567, U.S. Pat. No. 4,547,289, EP-A-0,138,060, or EP-A-0,732,142, for example.
All dead-end membrane modules have a disadvantage in that they are often not suited for the treatment of suspensions, for example, when the size of the particles contained in the suspension is on the order of magnitude of the pore diameter. The particles would lead to the formation of a coating on the membrane wall and block the membrane. For application in affinity separation processes for suspensions, for example, such dead-end modules can be driven only in combination with an upstream pre-cleaning stage. This causes a reduction of efficiency in such a process, in part also because in many cases a large portion of the target substance is lost by such pre-cleaning.
The cited disadvantages of modules operated in dead-end mode with respect to their usability with suspensions, for example, can in part at least be avoided by the use of cross-flow modules. With the latter, the accumulation of a layer of suspended particles can be reduced by the feed stream flowing parallel to the membrane surface if the shear stress is sufficiently high.
WO 90/05018 discloses a cross-flow module with hollow-fiber membranes for use with affinity separation processes. In this module, a ligate-containing liquid is introduced into the module housing via an inlet arrangement and flows tangentially over one side of the hollow-fiber membranes, in and on which the ligands have been coupled. A portion of the liquid permeates the membrane, whereby the ligates are attached to the ligands, and exits as a permeate stream on the side of the membrane opposite the inlet side. The retentate and permeate streams are removed via separate outlet arrangements.
A modified cross-flow process is described in WO 93/02777. For specific removal of components from blood, a plasma filter is used that is made from hollow-fiber membranes bended in a U-shape and embedded at their ends in a specially shaped housing. Blood flows through the lumina of the hollow-fiber membranes, and the substance-specific treatment is performed on the blood plasma, separated using the membrane, in the external space surrounding the hollow-fiber membranes in the housing, which contains a cleaning agent. The bundle can be divided into an inflow branch and an outflow branch. Due to the positive transmembrane pressure developing in the inflow branch, convective transport of blood plasma takes place through the membrane into the external space. In the outflow branch, the treated plasma flows, due to the developing negative transmembrane pressure, back into the lumina of the hollow-fiber membranes and is reunited with the blood.
In EP-A-0,341,413, an adsorber module for treating whole blood is described in which blood flows in cross-flow mode through the lumina of the hollow-fiber membranes contained in the module, embedded at both ends in sealing compound and provided with ligands. In this process, plasma passes through the hollow-fiber membrane wall as a permeate into the external space surrounding the hollow-fiber membranes, whereby the treatment of the plasma takes place in the membrane wall. In a special embodiment, this module has no outlet for the permeate; rather the plasma separated as a permeate collects in the external space surrounding the capillaries and, due to the developing pressure conditions, again passes through the hollow-fiber membrane wall into the lumen of the hollow-fiber membrane. Since the permeate stream must flow through the membrane wall twice in such a module design, this permeate stream and thus the portion of the plasma subjected to substance-specific treatment are relatively small. An additional result is that the required treatment times are relatively long.
The described modules operated in cross-flow mode exhibit various disadvantages. In the case of separate permeate and retentate streams, additional pumps and/or monitoring elements are required. Furthermore, production of the modules is complex as a result of embedding of the hollow-fiber membranes at both ends, and the portion of membranes that is without function with respect to the substance-specific treatment increases due to the embedding, more so as the module lengths decrease. Since in the case of cross-flow modules only a portion of the overall fluid to be treated is directed through the membrane, a series connection of multiple modules is often required. This, however, considerably increases the complexity of producing and operating the cross-flow modules in the prior art.